Recently, the biosensor, which uses a biological material recognition mechanism of biopolymer, has been used in medical and environmental analysis fields. The biosensor is obtained by combining the biological material recognition mechanism of biopolymer, an interfacial potential detection mechanism at an interface (also referred to as a solid-liquid interface) of a solution and an insulating film, and an electrical measurement device.
As the biological material recognition mechanism, substrate-specificity of enzyme, antibody-antigen reaction, a mutual operation between deoxyribonucleic acid (DNA) and DNA, a mutual operation between ribonucleic acid (RNA) and RNA, coupling of lectin and physiological active sugar chain, affinity of protein to specific biological material, and the like have been used.
As the interfacial potential detection mechanism, for example, an ion sensitive FET (FET sensor), in which a metal oxide semiconductor field effect transistor (MOSFET) is set as basic structure, has been used. The FET sensor measures an electric double-layer potential by detecting potential variation of electric double-layer that is formed at the solid-liquid interface as threshold voltage (Vth) shift of reference electrode potential-drain current characteristics (Vref-Id characteristics).
Examples of a main factor of causing the electric double-layer potential to vary include a phenomenon such as variation in potential of hydrogen (pH) in the solution, physical and chemical adsorption to the insulating film interface. For example, the relationship between the pH and the electric double-layer potential is known by electrochemical Nernst theory. For example, at 25° C., pH varies by 1 (this means that one order of magnitude of the hydrogen ion concentration in the solution is changed). The electric double-layer potential varies by approximately 59 mV due to the variation. This represents that 59 mV/pH is theoretical limit of sensor sensitivity in the pH sensor based on the electric double-layer potential.
The level of pH is useful index for bio-sensing. The biosensor causes the pH variation in the solution by decomposing the biological material through enzyme reaction, and by generating hydrogen ions as a by-product. In addition, the biosensor measures a concentration of the biological material by detecting the pH variation with the FET sensor. The biosensor has both molecular recognition and substrate decomposition function with enzyme, and pH measurement function with the FET sensor. Therefore, it is necessary for the molecular recognition and substrate decomposition function and the pH measurement function not to inhibit each other. In addition, a variation in the concentration of hydrogen ions that are generated through the enzyme reaction becomes lower than a concentration of original biological material. Therefore, so as to realize bio-sensing in which the pH variation is set as index, it is necessary to have a function capable of accurately detecting an extremely minute pH variation.
In the future, in clinical examination field, it is predicted that a demand for point of care testing (POCT), in which test is performed in the vicinity of test subject in medical field, will increase. This clinical examination is performed to grasp the concentration of specific biological material. In addition, in this clinical examination, it is considered that a demand for measurement of low-concentration material, which is not detected in an existing technology, will increase. To cope with this demand, the biosensor capable of performing high-sensitivity measurement is necessary.
Next, the descriptions will be given of technology (hereinafter, referred to as “related technology”) that relates to the disclosure.
With regard to the TFT biosensor, for example, there is reported case related to label-free detection of the DNA molecules and horseradish peroxidase molecules by using an amorphous silicon TFT (D. Goncalves, and three other persons, “Label-free electronic detection of biomolecules using a-Si:H field-effect devices”, “Journal of Non-Crystalline Solids”, ELSEVIER, Jun. 15, 2006, volume 352, p. 2007-2010). Furthermore, the TFT is an abbreviation of a thin film transistor. A linear Vth shift is obtained up to 0.4 μM in the DNA molecules, and up to 0.1 μM in the horseradish peroxidase molecules.
In the TFT biosensor in which a carbon nanotube is used in an active layer, there is disclosed an acetylcholine sensor in which acetylcholinesterase is fixed to an upper portion of the active layer (Wei Xue, and other one person, “A thin-film transistor based acetylcholine sensor using self-assembled carbon nanotubes and SiO2 nanoparticles”, “Sensors and Actuators B: Chemical”, ELSEVIER, Sep. 25, 2008, volume 134, p. 981-987). As sensitivity, resolution, and response time, values of 378.2 μA/decade, 10 nM, and 15 seconds are obtained, respectively.
As known example in which the enzyme reaction is used, there is reported the penicillin sensor in which penicillin oxidase is fixed to an ion-sensitive film of FET sensor (A. Poghossian, and other four persons, “An ISFET-based penicillin sensor with high sensitivity, low detection limit and long lifetime”, “Sensors and Actuators B: Chemical”, ELSEVIER, Jun. 1, 2001, volume 76, p. 519-526). The penicillin sensor has the configuration in which pH is allowed to vary by decomposing penicillin with the enzyme, and by generating hydrogen ions as by-product, and the pH variation is detected by FET sensor. As detection sensitivity, 120±10 mV/mM is obtained, and a continuous operation of one year or longer is confirmed.
In addition, as biosensor including a field effect transistor, the following case is reported. Specifically, a reaction field, to which a detection object material recognition molecule is fixed on one surface of a silicon substrate, and a field effect element which is formed on the other surface of the silicon substrate as a detection unit, are provided so as to attain an improvement in detection sensitivity (Japanese Patent Application Laid-Open No. 2013-148456).
In addition, there is disclosed an example of biosensor in which a vertical transistor is used as transducer, and the enzyme and antibody, which have a molecule recognition function, are fixed to porous alumina, and which indicates a possibility of high-speed response operation (Japanese Patent Application Laid-Open No. 2010-151540).